Effective treatments for cancer are a major challenge among researchers and there is a need for new therapies targeting abnormal proliferative disorders. The presence of hypoxic areas in solid cancers has been correlated with resistance to chemotherapy and radiation treatment. Hypoxia inducible factors (HIFs) are transcription factors that activate genes controlling mechanisms such as glycolysis, erythropoiesis, angiogenesis, epithelial to mesenchymal transition, and cell motility and invasion/metastasis, which can benefit the survival of cancer cells. HIFs are heterodimeric protein complexes, composed of HIF1-α and HIF1-β subunits, which then associate with cofactors such as p300 and CBP to form active transcription factors. The regulation of HIFs largely occurs at the protein level, and is dependent upon the synthesis and stability of the HIF1-α subunits. Under normoxia, HIF1-α subunits are hydroxylated at proline residues by oxygen-dependent prolyl hydroxylases (PHDs), which mediates recognition by the Von Hippel-Lindau (VHL) E3 ubiquitin ligase complex and rapid degradation by the proteasome. Under hypoxia, HIF1-α subunits are stabilized due to the inhibition of proline hydroxylation, and a functional HIF transcriptional complex is assembled, translocates to the nucleus, and transcribes genes that contain DNA sequences called hypoxia response elements (HREs). Elevated levels of HIF-1α have been correlated with poor prognosis of patients with cancers.
Tumor cells overexpressing HIFs represent an important target for antitumor therapy. Zhang et al. report digoxin and other cardiac glycosides inhibit HIF-1 alpha synthesis and block tumor growth. PNAS, 2008, 105(50):19579-19586. A number of existing chemotherapeutics can alter HIF activity including 2ME2, 17-DMAG, 17-AAG, camptothecin, PX-478, and YC-1. Ellinghaus et al. report that BAY 87-2243 inhibits HIF-1α Cancer Medicine, 2013, 2(5): 611-624. Antitumor activity of BAY 87-2243 in vivo was demonstrated in a H460 xenograft model. BAY 87-2243 also inhibits mitochondrial complex I activity. Interference with mitochondrial function to reduce hypoxia-induced HIF-1 activity in tumors is indicated as a therapeutic approach to overcome chemo- and radiotherapy resistance of hypoxic tumors.
A number of patent applications report small molecules for use in the treatment of hypoxia related pathologies (see e.g. US Published Application 2013-0164218, WO 2004/087066, WO 2007/025169, WO 2010/006184, and WO 2010/006189). See also Sato et al., 2000, Proc Natl Acad Sci USA, 97:10832-10837; Whitesell et al., 1994, Proc Natl Acad Sci USA., 91:8324-8328; Zhou et al. 2004, J. Biol. Chem. 279:13506-13513; Katschinski et al., 2002, J. Biol. Chem. 277:9262-9267 and Isaacs et al., 2002, J Biol Chem., 277:29936-44).
References cited herein are not an admission of prior art.